Prenatal cocaine exposure (PCE) is related to cognitive and behavioral deficits in infancy, childhood and adolescence, however findings are diverse and inconsistent across studies, and the postnatal environment plays a powerful role in such developmental outcomes. MRI studies in childhood and adolescence report similarly inconsistent effects of PCE on brain structure, activation and links to behavior. Although gestational exposure occurs during a time of extraordinary brain growth and organization, and the months following birth are marked by massive expansion of brain structure and connectivity, little is known about the effects of PCE on early human brain development that may contribute to reported deficits in cognitive function. The long term goal is to understand prenatal effects of cocaine exposure on early development of brain structure and function, and to discern how postnatal factors may protect or further harm growth and connectivity of structures underlying nascent cognitive abilities. The objectives of this proposal are to quantify the effects of PCE on the developmental trajectory of infant brain structure in postnatal months 1-9, to determine the extent to which gray and white matter (GM, WM) growth trajectories contribute to the effects of PCE on early cognitive function, and to identify maternal factors that moderate these effects. The central hypothesis is that fetal brain development is impaired by PCE; deficits in GM and WM growth and connectivity mediate the effect of PCE on simultaneously developing early cognitive skills; and postnatal maternal behaviors interact with PCE to influence growth of brain structure and function. This hypothesis is based on the applicant's strong preliminary data showing reduced cortical prefrontal and frontal GM volume and connectivity in cocaine-exposed neonates compared with drug-free infants and infants exposed to other drugs (nicotine, marijuana, alcohol, opiates), and inverse association between prefrontal GM volume and duration of gestational cocaine exposure. The rationale for this research is that longitudinal study will determine whether the postnatal trajectory of brain growth is merely delayed or permanently altered by PCE, ascertain postnatal factors that contribute to greater risk or resilience in developing brain, and suggest new mechanisms and targets for earlier intervention. The hypothesis will be tested with three Specific Aims: 1) Determine effects of PCE on developmental trajectories of infant brain structure; 2) Determine the extent to which the effects of PCE on early cognitive functions are predicted by GM and WM developmental trajectories; 3) Determine the moderating effects of maternal behavior on brain development. The approach is innovative because it will integrate maternal behavioral and physiological responses to infant with neonatal brain imaging proximal to in utero exposure, in order to quantify the direct and interactive effects of initial neural deficit and postnatal environment on subsequent patterns of brain and cognitive development. The proposed research is significant because knowledge gleaned has potential to inform earlier interventions to prevent or reduce cognitive disabilities i this vulnerable population.